The goal of the parent grant is to investigate the role of Notch signaling in inflammatory osteoporosis. We found that persistent activation of Notch in mesenchymal stem/progenitor cells limits their osteoblast (OB) differentiation potential and causes bone loss, which can be prevented by Notch inhibitors, DAPT and Thapsigarin [1]. Our findings suggest that Notch inhibitors could be used as bone anabolic agents. However, Notch inhibitors have severe adverse effects due to systemic distribution [2], limiting their use in common diseases such as osteoporosis. Thus, making bone targeted Notch inhibitors to reduce their systemic side effects will be a very attractive approach. In this revision, we will form a ne interdisciplinary team including a Bone Biologist (Dr. Xing, the PI of the parent grant) and Chemists (Dr. Boeckman, a co-PI of the revision; Dr. Ebetino, consultant of the revision) to design and synthesize bone targeted Bortezomib by conjugating it to a bisphosphonate using a novel carbamate linker that will release Bortezomib from the Bortezomib- bisphosphonate. Two special aims are proposed. In aim 1, we will design and synthesize bone-targeted Bortezomib conjugates and in aim 2, we will examine the bioactivity of bone-targeted Bortezomib conjugates in OB cultures and in mouse fracture healing. If we are successful, we will use a similar approach to synthesize bone targeted Notch inhibitors to reduce their toxic effects in the treatment of inflammatory osteoporosis, a main goal of the parent grant, and perhaps in other bone loss related to inflammation. The application will also lead to new directions for both Drs. Xing and Boeckman's lab: understanding the role of the ubiquitin- proteasome system in bone fracture repair in the aged population with a focus on mesenchymal stem/progenitor cells (Xing's lab); and using a novel chemical linker in other drugs and compounds, which will open a new strategy of bone targeting chemistry (Boeckman's lab).